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Introduction: The current study aimed to investigate the rates of anxiety, clinical depression, and suicidality and their changes in health professionals during the COVID-19 outbreak. Materials and methods: The data came from the larger COMET-G study. The study sample includes 12,792 health professionals from 40 countries (62.40% women aged 39.76 ± 11.70; 36.81% men aged 35.91 ± 11.00 and 0.78% non-binary gender aged 35.15 ± 13.03). Distress and clinical depression were identified with the use of a previously developed cut-off and algorithm, respectively. Statistical analysis: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses, and Factorial Analysis of Variance (ANOVA) tested relations among variables. Results: Clinical depression was detected in 13.16% with male doctors and ‘non-binary genders’ having the lowest rates (7.89 and 5.88% respectively) and ‘non-binary gender’ nurses and administrative staff had the highest (37.50%); distress was present in 15.19%. A significant percentage reported a deterioration in mental state, family dynamics, and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (24.64% vs. 9.62%; p < 0.0001). Suicidal tendencies were at least doubled in terms of RASS scores. Approximately one-third of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop clinical depression was associated with a history of Bipolar disorder (RR = 4.23). Conclusions: The current study reported findings in health care professionals similar in magnitude and quality to those reported earlier in the general population although rates of clinical depression, suicidal tendencies, and adherence to conspiracy theories were much lower. However, the general model of factors interplay seems to be the same and this could be of practical utility since many of these factors are modifiable. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.

Fountoulakis K.N., Karakatsoulis G.N., Abraham S., Adorjan K., Ahmed H.U., Alarcón R.D., Arai K., Auwal S.S., Berk M., Bjedov S., Bobes J., Bobes-Bascaran T., Bourgin-Duchesnay J., Bredicean C.A., Bukelskis L., Burkadze A., Abud I.I.C., Castilla-Puentes R., Cetkovich M., Colon-Rivera H., Corral R., Cortez-Vergara C., Crepin P., De Berardis D., Delgado S.Z., De Lucena D., De Sousa A., Stefano R.D., Dodd S., Elek L.P., Elissa A., Erdelyi-Hamza B., Erzin G., Etchevers M.J., Falkai P., Farcas A., Fedotov I., Filatova V., Fountoulakis N.K., Frankova I., Franza F., Frias P., Galako T., Garay C.J., Garcia-Álvarez L., García-Portilla M.P., Gonda X., Gondek T.M., González D.M., Gould H., Grandinetti P., Grau A., Groudeva V., Hagin M., Harada T., Hasan T.M., Hashim N.A., Hilbig J., Hossain S., Iakimova R., Ibrahim M., Iftene F., Ignatenko Y., Irarrazaval M., Ismail Z., Ismayilova J., Jacobs A., Jakovljević M., Jakšić N., Javed A., Kafali H.Y., Karia S., Kazakova O., Khalifa D., Khaustova O., Koh S., Kopishinskaia S., Kosenko K., Koupidis S.A., Kovacs I., Kulig B., Lalljee A., Liewig J., Majid A., Malashonkova E., Malik K., Malik N.I., Mammadzada G., Mandalia B., Marazziti D., Marčinko D., Martinez S., Matiekus E., Mejia G., Memon R.S., Martínez X.E.M., Mickevičiūtė D., Milev R., Mohammed M., Molina-López A., Morozov P., Muhammad N.S., Mustač F., Naor M.S., Nassieb A., Navickas A., Okasha T., Pandova M., Panfil A.-L., Panteleeva L., Papava I., Patsali M.E., Pavlichenko A., Pejuskovic B., Da Costa M.P., Popkov M., Popovic D., Raduan N.J.N., Ramírez F.V., Rancans E., Razali S., Rebok F., Rewekant A., Flores E.N.R., Rivera-Encinas M.T., Saiz P., de Carmona M.S., Martínez D.S., Saw J.A., Saygili G., Schneidereit P., Shah B., Shirasaka T., Silagadze K., Sitanggang S., Skugarevsky O., Spikina A., Mahalingappa S.S., Stoyanova M., Szczegielniak A., Tamasan S.C., Tavormina G., Tavormina M.G.M., Theodorakis P.N., Tohen M., Tsapakis E.M., Tukhvatullina D., Ullah I., Vaidya R., Vega-Dienstmaier J.M., Vrublevska J., Vukovic O., Vysotska O., Widiasih N., Yashikhina A., Prezerakos P.E., Smirnova D.

Recent success of established treatment has driven concerns about the ethics of using placebo-controlled trials in psychiatry. Active-controlled (superiority or non-inferiority) trials do not include a placebo-arm and thus avoid the associated ethical concerns but show disadvantages in other respects. The aim of this paper is to review the available literature and critically discuss the evidence regarding the use of placebo-controlled- versus active-controlled trials. A MEDLINE/PubMed and Google Scholar search was performed. Studies included focused on the deliberation on placebo-controlled- versus active-controlled trials. Twenty-six studies were included. The most cited benefits of placebo-controlled trials were greater scientific reliability of the results and no average impact on patients' health. Disadvantages were mainly related to withholding effective treatment and limited generalizability. The most frequent argument in favor of active-controlled trials is the lower chance of receiving ineffective medication during the trial. Downsides include larger sample sizes, higher costs and lower scientific reliability of results. Most authors agree that all trial designs are relevant to psychiatric research depending on study goals. Whatsoever, data does not support forgoing placebo-controlled trials. Expert consensus is warranted to permit drawing conclusions on the debate on the relevance of placebo-controlled trials.

Background Cognitive dysfunction represents a distinct biological and clinical dimension in major depression disorders (MDD) and cognitive performance strongly affects psychosocial functioning in patients diagnosed with MDD. Objective To assess which neurocognitive variables at baseline predict the functional outcome of MDD patients in a 1-year follow-up study as assessed by Functioning Assessment Short Test (FAST) and whether the improvement observed on affective and cognitive symptoms in our 12 week-prospective observational study after treatment with selective serotonin reuptake inhibitors (SSRIs) and selective noradrenalin reuptake inhibitors (SNRIs) can affect the following long-term psychosocial functional outcome at 1 year in the same MDD patients. Methods We recruited a total of 31 patients (8 males; 23 females) with MDD who had previously completed a pharmacological treatment with SSRIs (n = 22) or SNRIs (n = 9) for 12 weeks, and then continued the same pharmacological treatment for 1 year. After an average 1-year follow-up, they were interviewed with the FAST to assess functional outcome. Multivariate analyses were applied to identify clinical and neurocognitive predictors of functional outcome. Results Total Montreal Cognitive Assessment (MoCA), Digit Span forward (Span F) and backward (Span B), and 15 Rey words immediate recall (Rey I) scores significantly correlated with FAST. However, after performing regression models only Rey immediate recall score was useful to predict long-term functional outcome (Pearson correlation coefficient R= -0.68, p

Background The concept of predominant polarity (PP) is defined as presenting more symptoms of one polarity. Previous studies have defined PP as one polarity (either a depression or mania episode) occurring during at least two-thirds of the lifetime. Methods We conducted an observational study with the COPE-BD (Clinical Outcome and Psycho-Education for Bipolar Disorder, Clinical Outcome Measures Section) dataset to identify the diagnostic and treatment differences between bipolar disorder (BD) patients with and without PP. Results The final sample included 210 BD-I (59.0%) and 146 BD-II (41.0%) patients. Of these, 28.9% patients presented predominant polarity (PP): 62 (17.4%) of those patients were depressed polarity predominant (DPP), 41 (11.5%) were manic polarity predominant (MPP), and 253 (71.1%) met criteria for bipolar disorders but did not present with PP. In comparison to this group of BD patients with undetermined polarity, the group of BD patients with PP presented more rapid cycling. Furthermore, in the undetermined polarity group, the onset of illness occurred earlier, and the duration of the illness was longer, with more hypomanic/manic and depressive episodes than patients who met the PP criteria. Limitations This study has a naturalistic and retrospective design and does not allow a specific follow-up of polarity over time. Conclusions These different clinical characteristics underline the importance of considering PP in patients with BD, and justify the need for differential treatment approach which could have an impact on patients' prognosis. Yet, more independent and prospective research is needed to confirm these findings, especially with the new classification of DSM-5 concerning mixed states.

Current mental health services across the world remain expert-centric and are based on traditional workflows, mostly using impractical and ineffective electronic record systems or even paper-based documentation. The international network for digital mental health (IDMHN) is comprised of top-level clinicians, regulatory and ICT experts, genetic scientists, and support organizations. The IDMHN has been formed to enable the implementation of digital innovations in clinical practice, hereby facilitating the transformation of current mental health services to be more personalized and more responsive to patients and healthcare needs. This consensus statement summarizes the consortium’s vision and strategy for further development of digital mental health.

Introduction: There are few published empirical data on the effects of COVID-19 on mental health, and until now, there is no large international study. ----- Material and methods: During the COVID-19 pandemic, an online questionnaire gathered data from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively. ----- Statistical analysis: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses and Factorial Analysis of Variance (ANOVA) tested relations among variables. ----- Results: Probable depression was detected in 17.80% and distress in 16.71%. A significant percentage reported a deterioration in mental state, family dynamics and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (31.82% vs. 13.07%). At least half of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop depression was associated with history of Bipolar disorder and self-harm/attempts (RR = 5.88). Suicidality was not increased in persons without a history of any mental disorder. Based on these results a model was developed. ----- Conclusions: The final model revealed multiple vulnerabilities and an interplay leading from simple anxiety to probable depression and suicidality through distress. This could be of practical utility since many of these factors are modifiable. Future research and interventions should specifically focus on them.

Diagnostic criteria for a major depressive episode capture heterogeneous presentations across unipolar (UD) and bipolar (BD) and first-onset (FDE) depression. We evaluated the contribution of each depressive and (hypo)manic symptom to worse functioning in UD/BD/FDE subgroups.A post-hoc analysis of the BRIDGE-II-Mix study. Acutely depressed patients were stratified into UD, BD and FDE. Each (hypo)manic or depressive symptom was included in a diagnosis-specific logistic regression model with functioning as dependent variable. Better/worse functioning was set with median diagnosis-specific GAF scores cutoffs. All p values were two-tailed. Statistical significance was set at p 0.05.A total of 2768/2811 depressed individuals were enrolled. In BD (N = 716), "recurrent thoughts of death" (OR 2.48, p 0.0001) and "feelings of worthlessness" (OR 2.28, p 0.0001) among depressive symptoms, "aggressiveness" (OR 1.67, p = 0.022) as the unique (hypo)manic symptom, significantly contributed to worse functioning. In UD (N = 1357), "depressed mood" (OR 5.6, p = 0.031) and "diminished interest or pleasure" (OR 4.77, p 0.0001) among depressive, "grandiosity" (OR 3.5, p = 0.014) among (hypo)manic symptoms, most significantly contributed to worse functioning. In FDE (N = 677) "recurrent thoughts of death" (OR 1.99, p 0.0001) and "insomnia/hypersomnia" (OR 1.88, p = 0.039) among depressive, "grandiosity" (OR 5.98, p = 0.038) as (hypo)manic symptoms significantly contributed to worse functioning.The post-hoc and cross-sectional design do not allow for prognostic or causal inferences.Key depressive and (hypo)manic symptoms distinctively associate with worse functional outcome in acute depression, with differential diagnostic-specific magnitude of effect. Core depressive symptoms are associated with worse functioning in unipolar depression, but not in bipolar or first-episode depression.

A cross-diagnostic, post-hoc analysis of the BRIDGE-II-MIX study was performed to investigate how unipolar and bipolar patients suffering from an acute major depressive episode (MDE) cluster according to severity and duration. Duration of index episode, Clinical Global Impression-Bipolar Version-Depression (CGI-BP-D) and Global Assessment of Functioning (GAF) were used as clustering variables. MANOVA and post-hoc ANOVAs examined between-group differences in clustering variables. A stepwise backward regression model explored the relationship with the 56 clinical-demographic variables available. Agglomerative hierarchical clustering with two clusters was shown as the best fit and separated the study population (n = 2314) into 65.73% (Cluster 1 (C1)) and 34.26% (Cluster 2 (C2)). MANOVA showed a significant main effect for cluster group (p p p

OBJECTIVES The "Bipolar Disorders: Improving Diagnosis, Guidance, and Education" (BRIDGE-II-Mix) study aimed to estimate the frequency of mixed states in patients with a major depressive episode (MDE) according to different definitions and to compare their clinical validity, looking into specific features such as rapid cycling (RC). METHODS Psychiatric symptoms, socio-demographic, and clinical variables were collected from a sample of 2811 MDE patients, of which 726 (25.8%) were diagnosed with bipolar disorder (BD). The characteristics of bipolar patients with RC (BD-RC) and without (BD-NRC) RC were compared. RESULTS Of 726 BD patients, 159 (21.9%) met DSM-5 criteria for RC. BD-RC group presented a higher number of lifetime depressive episodes (p

Relatives of people diagnosed with psychotic and affective disorders have a higher risk of developing psychiatric disorders compared to the general population. This study examined the risk of hospitalization for psychiatric disorders among siblings and parents of patients affected with major psychiatric disorders. In this large population-based case-control study, 17,895 siblings and parents of 7671 hospitalized subjects with a diagnosis of narrowly defined schizophrenia (SZ), broadly defined SZ, schizoaffective disorder (SAD), bipolar disorder (BD) or unipolar depression (UD) were identified from the Israeli Psychiatric Hospitalization Registry and compared to 71,580 age and gender-matched controls from the Israeli Population Registry. Results indicated that siblings of people diagnosed with broadly defined SZ had a significantly higher risk of hospitalization for broadly (OR=11.06, 95% CI=7.93-15.41) and narrowly defined SZ (OR=10.59, 95% CI=6.8-16.33), SAD (OR=9.69, 95% CI=4.76-19.73), BD (OR=7.46, 95% CI=21.8-25.52), UD (OR=2.84, 95% CI=1.01-8.00), and other psychiatric disorders (OR=1.85, 95% CI=1.16-2.93), compared to controls. Siblings of patients with BD had a significantly higher risk of hospitalization for broadly defined SZ (OR=2.92, 95% CI=1.11-7.71) and for other psychiatric disorders (OR=6.67, 95% CI=2.17-20.50), compared to controls. Parents of probands with SZ were at significantly increased risk for all disorders examined, except for UD and ¨other psychiatric disorders¨, which was not significant in parents of probands with BD. This large, population-based study provides evidence for common genetic risk across different psychiatric disorders.

Major Depressive Episode (MDE) is a transdiagnostic nosographic construct straddling Major Depressive (MDD) and Bipolar Disorder (BD). Prognostic and treatment implications warrant a differentiation between these two disorders. Network analysis is a novel approach that outlines symptoms interactions in psychopathological networks. We investigated the interplay among depressive and mixed symptoms in acutely depressed MDD/BD patients, using a data-driven approach. We analyzed 7 DSM-IV-TR criteria for MDE and 14 researched-based criteria for mixed features (RBDC) in 2758 acutely depressed MDD/BD patients from the BRIDGE-II-Mix study. The global network was described in terms of symptom thresholds and symptom centrality. Symptom endorsement rates were compared across diagnostic subgroups. Subsequently, MDD/BD differences in symptom-network structure were examined using permutation-based network comparison test. Mixed symptoms were the most central and highly interconnected nodes in the network, particularly agitation followed by irritability. Despite mixed symptoms, appetite gain and hypersomnia were significantly more endorsed in BD patients, associations between symptoms were highly correlated across MDD/BD (Spearman's r = 0.96, p0.001). Network comparison tests showed no significant differences among MDD/BD in network strength, structure, or specific edges, with strong edges correlations (0.66-0.78). Upstream differences in MDD/BD may produce similar symptoms networks downstream during acute depression. Yet, mixed symptoms, appetite gain and hypersomnia are associated to BD rather than MDD. Symptoms during mixed-MDE might aggregate according to 2 different clusters, suggesting a possible stratification within mixed states. Future symptom-based studies should implement clinical, longitudinal, and biological factors, in order to establish tailored therapeutic strategies for acute depression.

Twin studies are among the most promising strategies for studying heritable disorders, including bipolar disorder (BD). The aim of the present study was to identify distinguishing genes between monozygotic (MZ) twins with different BD phenotype and compare them to their non-affected siblings. Whole-exome sequencing (WES) can identify rare and structural variants that could detect the polygenetic burden of complex disorders. WES was performed on a family composed of two MZ twins with BD, their unaffected brother and unaffected parents. The twins have a discordant response to lithium and distinct course of illness. Following WES, six genes of particular interest emerged: Neurofibromin type 1 (NF1), Biorientation of chromosomes in cell division 1 (BOD1), Golgi-associated gamma adaptin ear-containing ARF binding protein 3 (GGA3), Disrupted in schizophrenia 1 (DISC1), Neuromedin U receptor 2 (NMUR2), and Huntingtin interacting protein 1-related (HIP1R). Interestingly, many of these influence glutamatergic pathways and thus the findings may have therapeutical implications. These results may provide important insights to unveil genetic underpinnings of BD and the response to lithium.

Background: Previous studies suggest that temperament features of adolescents may be good predictors of the development of future psychopathology in this population. The aim of the study was to adapt the content and validate the psychometric properties of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego - Auto-questionnaire in a sample of Serbian adolescents.Subjects and methods: The sample included 2113 adolescents, 56% girls and 44% boys, average age 16.73±0.47, attending 48 Serbian secondary schools. The base for the development of this scale included Serbian standardised versions as well as the TEMPSI, Interview version.Results: The final scale is comprised of 36 items, with six factors (depressive, cyclothymic, hyperthymic, irritable, and anxiouscognitive/somatic) explaining 39.9% of the total variance, the internal consistency coefficient Į=0.77, and the average test–retest coefficient (rho=0.84). The correlations among the temperaments ranged from weak to moderate, with the highest positive correlations between the depressive, cyclothymic and anxious scales. The highest values were detected on hyperthymic and the lowest on depressive temperament. Significantly higher scores of depressive, cyclothymic and anxious temperaments were detected in girls, whereas boys had higher scores on the hyperthymic scale.Conclusions: The scale has shown good psychometric properties, which encourages its further use in adolescent population. The results show certain specific features of this population, such as higher scores on all temperament types than the ones in student and adult population and a tendency of socially desirable answers.

Introduction Bipolar disorder (BD) is a highly heritable and disabling mental illness, commonly associated with substance abuse, being alcohol abuse the most frequent. Comorbid BD and substance abuse disorders are often associated with high levels of health service utilization and destabilization of the course of illness resulting in poor treatment outcomes. Although recent genome-wide association studies have detected a number of risk genes for BD, the data is still sparse and inconclusive for those genes that may contribute to the increased risk of comorbid alcohol abuse (AA) in BD. The primary aim of the present study was to investigate the effects of 46 single-nucleotide polymorphisms (SNPs) within eight genes on different phenotypes of BD patients, such as comorbid alcohol abuse. We further assessed clinical variables associated with AA. Methods One-hundred fifty-eight BD I and II patients were enrolled in a naturalistic cohort study. Genomic DNA of 92 patients was extracted from whole blood using standard procedures and 46 tag SNPs in eight genes of interest (ANK, CACNA1C, CACNB2, FKBP5, GRM7, ITIH3, SYNE1 and TCF4) were genotyped. Results Seventy-one patients out of 158 (45%) satisfied diagnostic criteria for comorbid AA. Among 46 SNPs analyzed, the only SNP associated with comorbid AA was rs1034936 polymorphism in the CANCA1C gene. This polymorphism was also associated with lifetime cocaine abuse, manic switch and current atypical antipsychotics. Conclusions Our findings suggest a role of rs1034936 CACNA1C gene variant in BD-AA group. Despite their preliminary nature, the present results may provide new insight on mechanisms underlying AA in BD.

The Bipolar Disorders: Improving Diagnosis, Guidance, and Education (BRIDGE-II-Mix) study aimed to estimate the frequency of mixed states in patients with a major depressive episode (MDE) according to different definitions and to compare their clinical validity, looking into specific features such as suicidality.A total of 2,811 subjects were enrolled in this multicenter cross-sectional study. Psychiatric symptoms, and sociodemographic and clinical variables were collected. The analysis compared the characteristics of patients with MDE with (MDE-SA group) and without (MDE-NSA) a history of suicide attempts.The history of suicide attempts was registered in 628 patients (22.34%). In the MDE-SA group, women (72.5%, p = 0.028), (hypo)mania in first-degree relatives (20.5%, p0.0001), psychotic features (15.1%, p0.0001), and atypical features (9.2%, p = 0.009) were more prevalent. MDE-SA patients' previous responses to treatment with antidepressants included more (hypo)manic switches [odds ratio (OR) = 1.97, 95% confidence interval (CI): 1.58-2.44, p0.0001], treatment resistance (OR = 2.07, 95% CI: 1.72-2.49, p0.0001), mood lability (OR = 1.98, 95% CI: 1.65-2.39, p0.0001), and irritability (OR = 1.80, 95% CI: 1.48-2.17, p0.0001). Multivariate analysis evidenced that risky behavior, psychomotor agitation and impulsivity, and borderline personality and substance use disorders were the variables most frequently associated with previous suicide attempts. In the MDE-SA group, 75 patients (11.9%) fulfilled Diagnostic and Statistical Manual (DSM)-5 criteria for MDE with mixed features, and 250 patients (39.8%) fulfilled research-based diagnostic criteria for a mixed depressive episode.Important differences between MDE-SA and MDE-NSA patients have emerged. Early identification of symptoms such as risky behavior, psychomotor agitation, and impulsivity in patients with MDE, and treatment of mixed depressive states could represent a major step in suicide prevention.

Background Schizophrenia (SZ) and bipolar disorder (BD) are traditionally distinguished on the basis of progressive deterioration and long-term outcome, but a more dimensional approach is warranted. There are limited data on the occurrence of manic symptoms in patients with schizophrenia. The aim of the current study was to search for patterns in the clinical symptomatology, which may suggest the presence of one or several mood disorders under the label of schizophrenia. Subjects and methods Hundred-seventy-five patients diagnosed with schizophrenia according to DSM-5 were included in the study. The psychometric assessment included the Positive and Negative Syndrome Scale, Young Mania Rating Scale, The Montgomery-Asberg Depression Rating Scale and the Calgary Depression Scale. The statistical analysis included MANOVA, Pearson Correlation coefficient and principal components analysis. Results Significant subthreshold manic symptoms were present in 25.14% of patients. Mood symptoms correlated with positive symptoms. The PCA revealed a complex structure with 15 factors (one positive, negative, somatic, anxiety, neurocognitive, disorganization and manic, five depressive and three psychomotor/excitement/hostility/violence). Conclusion Psychotic mood disorders are often phenotypically indistinguishable from schizophrenia, so it is likely that psychotic affective patients have been misdiagnosed with schizophrenia. The current study suggests that there seem to be patients with mania misdiagnosed as 'schizophrenics' because of the presence of psychotic features, a condition better described as 'schizophreniform bipolar disorder'.

Due to the episodic and chronic nature of bipolar disorder, maintenance therapy represents a critical part of treatment. However, there is a paucity of studies comparing effectiveness of available long-term treatments. In this chapter, the efficacy and safety of pharmacological treatments for maintenance treatment of bipolar disorder, as deriving from the results of randomized controlled trials, will be critically reviewed. These include second-generation antipsychotics aripiprazole, olanzapine, quetiapine, risperidone long-acting injection, ziprasidone, paliperidone, and mood stabilizers lamotrigine, lithium, valproate, carbamazepine, and oxcarbazepine. In general, if a patient has responded satisfactorily to a certain drug during the acute phase, the same treatment should be maintained during maintenance treatment. This was confirmed in two randomized controlled trials. This chapter summarizes the characteristics of the placebo-controlled randomized controlled trials for all the antipsychotics used for maintenance treatment of bipolar disorder.

Several psychological interventions-including group psychoeducation, family-focused psychoeducation, and interpersonal social-rhythm therapy-have demonstrated prophylactic efficacy as an adjunct to medication in bipolar disorders (BDs). The field of psychological interventions for BD has experienced impressive progress over the last 15 years. Certain unexplored areas, however, require further research in order to establish the full potential of psychological interventions for BD. Such research should focus, among other things, on cognitive impairment associated with BD, BD in the elderly, comorbid anxiety disorders and other comorbidities, the treatment of BD in pregnant women, and the improvement of patients' overall physical health.

Discrepancies between bipolar patients' reports and neuropsychological testing have been described and replicated. Unfortunately, no valid, specific, user-friendly, brief instrument is available to measure cognitive deficits as reported by these patients. The main aim of this study was to validate a novel instrument named the "cognitive complaints in bipolar disorder rating assessment" (COBRA). Second, we investigated the relationship between the COBRA, objective cognitive measures and illness course variables.The total sample (N=215) included 91 bipolar disorder patients and 124 healthy controls. The psychometric properties of the COBRA (e.g. internal consistency, concurrent validity, discriminative validity, factorial analyses, ROC curve and feasibility) were analyzed. A complete neuropsychological battery was used as objective cognitive assessment.The COBRA had one-factor structure with very high internal consistency (Cronbach's alpha=0.913). A high convergent validity was indicated by a strong correlation with the Frankfurt Complaint Questionnaire (ro=0.888, p0.001). Bipolar patients experienced greater cognitive complaints compared to control group suggesting a discriminative validity of the instrument. Significant correlations were found between the COBRA and some objective cognitive measures. Furthermore, higher COBRA scores were associated with bipolar II subtype, residual depressive symptoms, hypomanic episodes and total episodes.The cross-sectional design of the study, the influence of medication and severity of patients included.The COBRA showed to be a useful instrument to assess overall cognitive complaints in bipolar disorder with very satisfactory psychometric properties. Cognitive complaints were partially correlated with memory and executive function measures and with issues that may increase the subjective perception of cognitive deficits, such as subthreshold depressive symptoms and number of episodes.

Objective Predominant polarity (PP) is an important variable in maintenance treatment of bipolar disorder (BD). This study aimed at determining the role of polarity index (PI), a metric indicating antimanic versus antidepressive prophylactic potential of drugs, in clinical decision-making. Method Two hundred and fifty-seven of 604 (43%) of patients with BD-I or II fulfilled criteria for manic (MPP) or depressive PP (DPP). The PI, representing the ratio of number needed to treat (NNT) for depression prevention to NNT for mania prevention, was calculated for patients' current treatment. MPP and DPP groups were compared regarding sociodemographic, clinical and therapeutic characteristics. Results One hundred and forty-three patients (55.6%) fulfilled criteria for DPP and 114 (44.4%) for MPP. Total PI, Antipsychotics' PI, and mood stabilizers PI were higher, indicating a stronger antimanic action, in MPP. MPP presented higher prevalence of BD-I, male gender, younger age, age at onset and at first hospitalization, more hospitalizations, primary substance misuse, and psychotic symptoms. DP correlated with BD-II, depressive onset, primary life events, melancholia, and suicide attempts. Conclusion The results confirm the usefulness of the PI. In this large sample, clinical differences among these groups justify differential treatment approach. The PI appears to be a useful operationalization of what clinicians do for maintenance therapy in BD.

Background: Although several adjunctive psychological interventions are effective in the maintenance of bipolar disorders (BD), no attempt has been made to classify them according to their ability to prevent manic versus depressive episodes. Our study aims to rank the adjunctive psychotherapies for the prophylaxis of BD by means of their polarity index (PI). Methods: Randomized controlled trials comparing the efficacy of a psychological intervention with a comparator in BD maintenance treatment in patients aged over 18 were systematically reviewed. Exclusion criteria were a small sample size, a study sample not exclusively composed of bipolar patients and the absence of a control group. PI is a novel metric indicating the relative antimanic versus antidepressive preventive efficacy of treatments. PI was retrieved by calculating the ratio of the number needed to treat (NNT) for prevention of depression and the NNT for prevention of mania. PI >1.0 indicates a relatively higher antimanic prophylactic efficacy and PI Results: A total of 9 studies were included. PI was 0.33, 0.63 and 0.89 for cognitive-behavioral therapy, 0.42 for family-focused therapy, 0.73 and 0.78 for psychoeducation, 1 for enhanced relapse prevention, 1.78 for caregiver group psychoeducation and 3.36 for brief technique-driven interventions. With regard to the PI for 1 cognitive-behavioral study, enhanced relapse prevention and brief technique-driven interventions may not be reliable since those trials were negative. Conclusions: The PI provides a measure of how much depression-preventive or (hypo) mania-preventive an intervention is and may guide the choice of adjunctive psychotherapy in the context of individualized long-term treatment of BD.

Multiple novel biological mechanisms putatively involved in the etiology of bipolar disorders are being explored. These include oxidative stress, altered glutamatergic neurotransmission, mitochondrial dysfunction, inflammation, cell signaling, apoptosis and impaired neurogenesis. Important clinical translational potential exists for such mechanisms to help underpin development of novel therapeutics - much needed given limitations of current therapies. These new mechanisms also help improve our understanding of how current therapeutics might exert their effects. Lithium, for example, appears to have antioxidant, immunomodulatory, signaling, anti-apoptotic and neuroprotective properties. Similar properties have been attributed to other mood stabilizers such as valproate, lamotrigine, and quetiapine. Perhaps of greatest translational value has been the recognition of such mechanisms leading to the emergence of novel therapeutics for bipolar disorders. These include the antioxidant N-acetylcysteine, the anti-inflammatory celecoxib, and ketamine - with effects on the glutamatergic system and microglial inhibition. We review these novel mechanisms and emerging therapeutics, and comment on next steps in this space.

Bipolar disorder is a severe mental illness that affects nearly 4.4% of the general population when bipolar spectrum disorders are taken into account. Neurocognitive impairment is thought to be a core deficit of this illness since it is present during euthymia. In fact, 40–60% of euthymic patients present with neurocognitive disturbances. Not only the clinical factors but also disturbances in neurocognition can influence the functional outcome of BD patients. Hence, further research is needed in order to clarify the relationship between these variables. Despite the growing body of evidence that has emerged during the last decade, no unique neurocognitive profile has been proposed yet for either BD subtype. The majority of the studies recluted heterogeneous samples (including both bipolar I and II) or focused on BD‐I patients only. The aim of this review is to give an overall picture of the main neurocognitive disturbances found in the bipolar spectrum and particularly in BD‐II, where the findings are more ambiguous. An extensive review of all the literature has been done regarding this subtype (from 1980 until July 2009). Data available until now suggest that deficits are present across the bipolar spectrum (BD‐I and BD‐II), but they seem slightly more severe in BD‐I. The extent to which either subtype share—or not—some similarities is still unknown. More studies are required but it would also be interesting to reach a consensus in the neuropsychological assessment of BD to facilitate comparisons between the different studies.

Rosa AR, Reinares M, Amann B, Popovic D, Franco C, Comes M, Torrent C, Bonnin CM, Sole B, Valenti M, Salamero M, Kapczinski F, Vieta E. Six-month functional outcome of a bipolar disorder cohort in the context of a specialized-care program. Bipolar Disord 2011: 13: 679–686. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: A marked disparity between functional recovery and symptomatic improvement has been demonstrated in bipolar disorder. However, most of the previous studies have been conducted in the United States, and there is little prospective research from Europe on this topic. The main objective of the present six-month follow-up study was to assess functioning in a sample of Spanish bipolar disorder patients following an acute episode or subsyndromal state. Additionally, we also evaluated the sensitivity to change of the Functioning Assessment Short Test (FAST). Methods: A total of 97 bipolar disorder patients with syndromal (n = 59) or subsyndromal (n = 38) symptoms were evaluated using the 17-item Hamilton Depression Rating Scale and Young Mania Rating Scale. The FAST was the primary measure to assess multiple areas of psychosocial functioning. Functioning was evaluated at four different time periods: baseline, 21 days, three months, and six months. Results: A significant improvement in global functioning was found in the whole sample over the six-month period, as indicated by a reduction of FAST total score (mean ± standard deviation) from 39.97 ± 15.10 to 30.65 ± 16.93 (F = 36.104, p = 0.0001). This was also evident in all areas of functioning studied. However, only 26.4% of remitted patients (n = 42) achieved functional recovery, while 79.6% of the total sample (N = 97) experienced clinical remission of acute symptoms. Conclusions: Although many patients presented syndromal recovery, only a minority of them achieved favorable functioning in multiple areas, even after specialized mental health care. Furthermore, the FAST scale was sensitive to detect minimal changes in functioning in both short (21 days) and long (6 months) periods, which may be relevant to the use of this scale in clinical trials.

Sole B, Bonnin CM, Torrent C, Balanza-Martinez V, Tabares-Seisdedos R, Popovic D, Martinez-Aran A, Vieta E. Neurocognitive impairment and psychosocial functioning in bipolar II disorder. Objective: There is a growing body of evidence on neurocognitive impairment in euthymic bipolar patients, but this issue has been studied mostly in bipolar I disorder, data on bipolar II (BD-II) are scant and discrepant. The two aims of this study were to ascertain whether strictly defined euthymic BD-II patients would present neurocognitive disturbances and to evaluate their impact on functional outcome. Method: Forty-three BD-II patients and 42 demographically and educationally matched healthy subjects were assessed with a comprehensive neuropsychological test battery and with the Social and Occupational Functioning Assessment Scale (SOFAS). The euthymia criteria were reduced (Hamilton Rating Scale for Depression score ≤6 and a Young Mania Rating Scale score ≤6) to minimize the influence of subdepressive symptomatology on cognition and functioning. Results: BD-II patients showed a significantly lower performance on several measures of attention, learning and verbal memory, and executive function compared with healthy controls. The presence of subthreshold depressive symptomatology and one measure related to executive function (Trail Making Test, part B) was the variables that best predicted psychosocial functioning measured with the SOFAS. Conclusion: This report provides further evidence that euthymic BD-II patients present cognitive impairment which may impact psychosocial functioning.

Although there are studies describing the prevalence of patients with drug addiction and dual diagnosis, there is a paucity of data regarding the progression from psychiatric disorders to drug addiction or vice versa. A total of 1,090 patients dependent on heroin were interviewed to examine the presence of dual diagnosis and the progression from psychiatric disorders to drug dependence or vice versa. A total of 574 patients met the criteria for a dual diagnosis. A total of 362 patients progressed from substance abuse disorders to psychiatric disorders (SUD-PR) and 144 patients progressed from psychiatric disorders to drug addiction (PSY-PR). SUD-PR patients are more frequently affected by mood disorders. PSY-PR patients were more frequently diagnosed as psychotic or affected by anxiety disorders. The authors' findings suggest that the self-medication theory of dual diagnosis was relevant only for those with existing diagnoses of schizophrenia or anxiety disorders. When treating patients with a dual diagnosis, clinicians should ensure that the same attention is given to the treatment of drug dependence as it is to the treatment of comorbid psychiatric conditions.

Valenti M, Pacchiarotti I, Rosa AR, Bonnin CM, Popovic D, Nivoli AMA, Murru A, Grande I, Colom F, Vieta E. Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients. Bipolar Disord 2011: 13: 145–154. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: The aim of this study was to elucidate the factors associated with the occurrence of mixed episodes, characterized by the presence of concomitant symptoms of both affective poles, during the course of illness in bipolar I disorder patients treated with an antidepressant, as well as the role of antidepressants in the course and outcome of the disorder. Method: We enrolled a sample of 144 patients followed for up to 20 years in the referral Barcelona Bipolar Disorder Program and compared subjects who had experienced at least one mixed episode during the follow-up (n = 60) with subjects who had never experienced a mixed episode (n = 84) regarding clinical variables. Results: Nearly 40% of bipolar I disorder patients treated with antidepressants experienced at least one mixed episode during the course of their illness; no gender differences were found between two groups. Several differences regarding clinical variables were found between the two groups, but after performing logistic regression analysis, only suicide attempts (p

Background Much of the literature has described personality disorder constructs for heroin addicts. Building on previous work we examine the relevance of affective temperament measures in these patients. Methods 59 consecutive stabilized methadone treated heroin addicts, 34 with and 25 without psychiatric comorbidity, were compared, regarding affective temperaments, according to the Akiskal and Mallya formulation, with 58 healthy volunteers sharing similar social and regional demographics. Results No differences were observed between heroin addicts and controls on either depressive or hyperthymic scales. Significant discrepancies were noted in cyclothymic and irritability scales, on which heroin addicts scored higher, regardless of the presence or absence of a dual diagnosis. In a multivariate discriminant analysis, mainly cyclothymic, and (to a lesser extent) irritable traits show a distinction between heroin addicts and controls, but not between heroin addicts with and without dual diagnoses. Limitation Cross-sectional study. Conclusion Our data suggest a new hypothesis. Cyclothymic, and to a lesser extent irritable traits (the “dark side”), could represent the temperamental profile of heroin addicts, largely irrespective of comorbidity, and tend to cohere with previous conceptualizations hypothesizing “sensation-seeking” (and “novelty-seeking”) as the main personality characteristics of addiction.

Mood stabilizers such as lithium and anticonvulsants are still standard-of-care for the acute and long-term treatment of bipolar disorder (BD). This systematic review aimed to assess the prevalence of their adverse effects (AEs) and to provide recommendations on their clinical management. We performed a systematic research for studies reporting the prevalence of AEs with lithium, valproate, lamotrigine, and carbamazepine/oxcarbazepine. Management recommendations were then developed. Mood stabilizers have different tolerability profiles and are eventually associated to cognitive, dermatological, endocrine, gastrointestinal, immunological, metabolic, nephrogenic, neurologic, sexual, and teratogenic AEs. Most of those can be transient or dose-related and can be managed by optimizing drug doses to the lowest effective dose. Some rare AEs can be serious and potentially lethal, and require abrupt discontinuation of medication. Integrated medical attention is warranted for complex somatic AEs. Functional remediation and psychoeducation may help to promote awareness on BD and better medication management.

Loxapine is an antipsychotic used in psychiatry for over 40 years with a well-established profile. Loxapine is a dibenzoxazepine tricyclic antipsychotic agent, available for oral, intramuscular and inhalatory administration. In the light of the recent approval by the regulatory agencies of inhaled loxapine for use in the acute treatment of mild-to-moderate agitation in adults affected with schizophrenia or bipolar disorder, this article aims to critically review the available literature on loxapine, irrespective of its formulation. This review examines the efficacy and tolerability of the various formulations of loxapine in the treatment of agitation and aggression in patients affected with schizophrenia, bipolar disorder and other psychiatric conditions. A comprehensive and systematic literature search of PubMed/MEDLINE was conducted, and relevant pharmacodynamic and pharmacokinetic data was included. The findings from the literature were critically reviewed and synthesized. The available data suggests that the antipsychotic efficacy of loxapine is similar to the efficacy of other typical or atypical antipsychotics, with an adverse effects profile comparable to that of the typical antipsychotics at high doses for chronic treatment. As an acute treatment in agitation associated with schizophrenia or bipolar disorder, inhaled loxapine was developed as an innovative and rapid option which appears to be efficacious and tolerable. Electronic supplementary material The online version of this article (doi:10.1186/s12991-015-0053-3) contains supplementary material, which is available to authorized users.

Objective To identify risk factors associated with suicide of patients with schizophrenia and provide clinical recommendations, which integrate research findings into a consensus based on clinical experience and evidence. Method A task force formed of experts and clinicians iteratively developed consensus through serial revisions using the Delphi method. Initial survey items were based on systematic literature review published up to June 2013. Results Various risk factors were reported to be implicated in suicide in schizophrenia. Our findings indicate that suicide risk in schizophrenia is mainly related to affective symptoms, history of a suicide attempt and number of psychiatric admissions. Other risk factors identified are given by younger age, closeness to illness onset, older age at illness onset, male sex, substance abuse and period during or following psychiatric discharge. Integrating the evidence and the experience of the task force members, a consensus was reached on 14 clinical recommendations. Conclusion Identification of risk factors for suicide in individuals diagnosed with schizophrenia is imperative to improve clinical management and develop strategies to reduce the incidence of suicide in this population. This study provides the critical overview of available data and clinical recommendations on recognition and management of the above-mentioned risk factors.

Background The present study aims to evaluate cognitive tolerability profile of SSRIs in long-term treatment. The secondary aim is to explore differences of side effects profile between patients with major depression (MD) and anxiety disorders (AD). Methods Sixty-seven consecutive patients, successfully treated with SSRIs in monotherapy for at least six months for MD or AD, were assessed for side effects, with a special focus on cognition. Results Over 20% of MD and AD patients in long term treatment with SSRIs reported cognitive symptoms including fatigue, inattentiveness, lack of concentration, memory impairment and apathy. Recall memory impairment, attention deficit and somnolence were most frequently rated as moderate or severe. There were no significant differences in SSRI cognitive side effects profile between MD and AD patients. Limitations Subjective measure of cognitive functioning, limited sample size, lack of a control group. Conclusions A large proportion of depressed and anxious patients treated successfully with SSRIs for over six months reported cognitive, affective, motivational symptoms. These symptoms are likely to represent SSRI side effects rather than residual depressive symptomatology.